Hypoxia inducible factors (HIFs) are transcription factors induced under a hypoxic condition which play an important role in the expression regulation of genes associated with energy metabolism, vasomotion regulation, angiogenesis and apoptosis, and cellular responses to changes in available oxygen in the cellular environment. Among the genes whose expression levels are regulated by HIFs are angiogenesis factors (VEGF, FLT1), glucose transports (Glut-1, Glut-3), and enzymes that take part in glycolysis (Nat. Rev. Cancer, 2003, 3: 721-732; J. Cell. Physiol., 2004, 200: 2030). The HIF transcription factor is a heterodimer comprised of two protein subunits, HIF-α and HIF-β. HIF-β is constitutively expressed while the expression of HIF-α is regulated by oxygen levels in the cellular environment. In the presence of normal oxygen tension, HIF-1α is hydroxylated at the two critical conserved proline residues of positions 402 and 564. Hydroxylated-HIF-1α can then bind the von Hippel-Lindau (VHL) tumor suppressor protein, which recruits the E3 ubiquitin-ligase complex to target the HIF-1α protein to promote proteasomal degradation. However, since oxygen is the rate-limiting co-factor for the hydroxylation, the prolyl hydroxylases are unable to hydroxylate HIF-1α at low oxygen tension. As a result, no VHL interaction occurs and the E3 ubiquitin-ligase complex is unable to target HIF-1α to proteasomal degradation, resulting in stabilization of HIF. Stabilized HIF-1α can then form a heterodimer with the HIF-1β, which is constitutively present within cells, and the heterodimer interacts with the hypoxia response element (HRE) on promoter regions of target genes, leading to the activation of hypoxia-responsive genes. In addition, the hydroxylation of an asparagine residue in the C-terminal transactivation domain (TAD) of HIF-1α (at position 803) by the factor inhibiting HIF-1 (FIH-1) negatively regulates the transcriptional activity of HIF by preventing its interaction with p300 and CBP transactivators. There are a large number of genes that have been known to be regulated by HIF, including genes associated with vascularization such as VEGF, Tie-2, Flt-1, Flk-1, PAI-1, EPO, and NOS, genes associated with metabolism under hypoxic conditions, such as GAPDH, Glut1, Glut3, LDH, HK-1, and HK-2, genes associated with apoptosis resistance, such as IGF-II, IGFBP-1, p21, NIP3, ADM, NOS2 and TGFA, and genes associated with the invasion and metastasis of tumor cells, such as SDF-1, CXCR4, β2 integrin, and prolyl-4-hydroxylase-α1.
Cancer refers comprehensively to diseases in which cells do not normally differentiate, but aberrantly grow to invade nearby parts of the body from its original site, thereby inhibiting normal functions of the tissues or organs. Particularly, rapidly propagating solid cancer takes place under hypoxic conditions because it is not supplied with as much oxygen and nutrients as it requires for its growth (J. Natl. Cancer Inst., 1989, 82: 4-6). Because solid cancer cells are adapted to a low oxygen condition after being subjected to various genetic alterations, they become more malignant and resistant to anticancer agents. In fact, hypoxia is known to play an important role in malignant cancer in over 70% of all cancer types (Nature, 1997, 386: 403-407; Semin. Oncol., 2001, 28: 36-41; Nat. Med., 2000, 6: 1335-1340; Cancer, 2003, 97: 1573-1581).
When activated by hypoxia, HIF-1 induces the expression of various genes encoding, for example, hexokinase 2, glucose transporter 1, erythropoietin, IGF-2 (insulin-like growth factor-2), endoglin, VEGF (vascular endothelial growth factor), MMP-2 (matrix metalloprotease 2), uPAR (uPA receptor), MDR1 (p-glycoprotein), etc., leading to an improvement in apoptosis resistance, angiogenesis, cell proliferation, and invasiveness, thereby resulting in the malignant transformation of cancer cells. Particularly, HIF-1α is known to exist at a much higher level in tumor tissues than in normal tissues (Cancer Res., 1999, 59: 5830-5835), and the expression level of HIF-1α is closely correlated with the clinical prognosis of cancer patients (Drug Disc. Today, 2007, 12: 853-859). Accordingly, it is well known that HIF inhibitors can be used as anticancer agents.
Based on this fact, active and extensive research has been conducted to develop anticancer agents targeting HIF (Cancer Res., 2002, 62: 4316-4324; Nat. Rev. Drug Disc., 2003, 2: 803-811; Nat. Rev. Cancer, 2003, 3: 721-732). Recently, a significant number of preexisting anticancer agents, such as taxol, rafamycin and 17-AAG (17-allylaminogeldanamycin), or small molecular compound YC-1 (guanylyl cyclase activator) are undergoing various clinical demonstrations to be used as HIF-1 inhibitors (Nat. Rev. Drug Disc, 2003, 2: 803-811; Nat. Rev. Cancer, 2003, 3: 721-732; J. Natl. Cancer Inst., 2003, 95: 516-525; Cancer Res., 62, 4316, 2002).
At the same time, HIF can be used as a target of therapeutics for diseases which are aggravated with angiogenesis as well as by cancer. Angiogenesis factors, such as VEGF, which are induced by HIF activated under hypoxic conditions are associated with the onset and progression of macular degeneration, diabetic retinopathy, arthritis and psoriasis as well as cancer. Hence, compounds inhibitory of HIF, which is activated by the hypoxic condition of the affected tissues, can be used as therapeutics for such diseases as macular degeneration, diabetic retinopathy, arthritis, etc. (Pathology International, 2005, 55: 603-610; Ann. Rheum. Dis., 2003, 62: ii60-ii67). Particularly, HIF-1α is reported to be involved in inflammatory responses (Cell, 2003, 112: 645-657). Because a joint with inflammation is under a hypoxic condition and HIF promotes inflammation and cartilage destruction and plays an important role in angiogenesis necessary for the onset of arthritis, HIF has been suggested as a target for the development of arthritis drugs (Ann. Rheum. Dis., 2005, 64: 971-980).
Leading to the present invention, intensive and thorough research into HIF inhibitors, conducted by the present inventors, resulted in the finding that specific α-arylmethoxyacrylate derivatives have excellent inhibitory activity against HIF.